1. Field of the Invention
The present invention relates to novel compounds having retinoid-like biological activity. More specifically, the present invention relates to 2,4-pentadienoic acid derivatives having selective activity for retinoid X (RXR) receptors.
2. Background Art
Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil(copyright), diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
Although pharmaceutical compositions containing retinoids have well established utility, retinoids also cause a number of undesired side effects at therapeutic dose levels, including headache, teratogenesis, mucocutaneous toxicity, musculoskeletal toxicity, dyslipidemias, skin irritation, headache and hepatotoxicity. These side effects limit the acceptability and utility of retinoids for treating disease.
It is now general knowledge in the art that two main types of retinoid receptorsexist in mammals (and other organisms). The two main types or families of receptors are respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RARxcex1, RARxcex2 and RARxcex3, in RXR the subtypes are: RXRxcex1, RXRxcex2 and RXRxcex3. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, among compounds having agonist-like activity at retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property. Some compounds bind to one or more RAR receptor subtypes, but do not trigger the response which is triggered by agonists of the same receptors. A compound that binds to a biological receptor but does not trigger an agonist-like response is usually termed an antagonist. Accordingly, the xe2x80x9ceffectxe2x80x9d of compounds on retinoid receptors may fall in the range of having no effect at all, (inactive compound, neither agonist nor antagonist) or the compound may elicit an agonist-like response on all receptor subtypes (pan-agonist). As still another alternative a compound may be a partial agonist and/or partial antagonist of certain receptor subtypes if the compound binds to but does not activate certain receptor subtype or subtypes but elicits an agonist-like response in other receptor subtype or subtypes. A pan-antagonist is a compound that binds to all known retinoid receptors but does not elicit an agonist-like response in any of the receptors.
Recently a two-state model for certain receptors, including the above-mentioned retinoid receptors, have emerged. In this model, an equilibrium is postulated to exist between inactive receptors and spontaneously active receptors which are capable of coupling with a G protein in the absence of a ligand (agonist). In this model, so-called xe2x80x9cinverse agonistsxe2x80x9d shift the equilibrium toward inactive receptors, thus bringing about an overall inhibitory effect. Neutral antagonists do not effect the receptor equilibrium but are capable of competing for the receptors with both agonists (ligands) and with inverse agonists.
Published PCT application WO 97/09297, assigned to the same assignee as the present application, describes several compounds having retinoid antagonist and retinoid inverse agonist type biological activity, and discloses that the above mentioned retinoid antagonist and/or inverse agonist-like activity of a compound is also a useful property, in that such antagonist or inverse agonist-like compounds can be utilized to block certain undesired side effects of retinoids, to serve as antidotes to retinoid overdose or poisoning, and may lend themselves to other pharmaceutical applications as well.
Numerous compounds having selective agonist-like activity for RXR retinoid receptors are described in published PCT applications WO 93/21146, WO 95/04036 and WO 97/12853. In these PCT publications specific compounds of particular interest as background to the present invention are, in the WO 93/21146 reference: 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)epoxy]benzoic acid, 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]benzoic acid, 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]pyridine-5-carboxylic acid and methyl 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]pyridine-5-carboxylate (Compounds 47, 48, 62 and Me-62 on pages 15 and 17 of WO 93/21146);
in the WO 95/04036 reference: (2E,4E)-3-methyl-5-[1-(3,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]penta-2,4-dienoic acid (Compound 104 on page 23 of WO 95/04036).
In the WO 97/12853 reference: tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 152); (2E,4E)-6-[2-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 153); (2E,4E)-6-[2-(5,5,8,8-tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 154); (2E,4E)-7-[(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 155); (2E,4E)-7-[(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 156); (2E,4E)-7-[(5,5,8,8-tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaphtha-1en-2-yl)cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 157); (2E,4E)-5-[2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopent-1-en-1-yl]-3-methyl pentadienoic acid (Compound 158); cis (2E,4E)-5-[2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydro-2-naphthyl)cyclopentan-1-yl]-3-methyl pentadienoic acid (Compound 159).
The following prior art compounds are also of interest to the present invention:
(2E,4E)-6-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 101); (2E,4E)-6-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 102); (2E,4E)-6-[(5,5,8,8-tetramethyl-3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 103); (2E,4E)-6-[(5,5,8,8-tetramethyl-3-ethoxy-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 104); (2E,4E)-6-[(3,5-di-t-butyl phenyl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 105); (2E,4E)-6-[(3,4-diethyl phenyl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 106); (2E,4E)-6-[1-(6-t-butyl-1,1-dimethyl-indan-4-yl)-cyclopropyl]-3-methyl hexadienoic acid (Compound 107); and (2E,4E)-6-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentane-1-yl]-3-methyl hexadienoic acid (Compound 108).
The publication WO 96/39374 published on Dec. 12, 1996 (corresponding to U.S. Pat. Nos. 5,663,367 and 5,675,033) describes 2,4-pentadienoic acid derivatives having selective activity for retinoid RXR receptors. The compounds of this reference include a condensed cyclic (tetrahydronaphthyl, chromanyl or thiochromanyl) moiety, and a cycloalkyl (primarily cyclopropyl) or phenyl or heteroaryl moiety linking the pentadienoic acid moiety to the condensed cyclic moiety.
U.S. Pat. No. 5,648,514 discloses phenylethynyl or heteroarylethynyl dihydronaphthalene derivatives where the 5 or 8 position (depending on the system of numbering) of the dihydronaphthalene nucleus is substituted with an alicyclic, aryl or heteroaryl group. U.S. Pat. No. 5,723,666 (formula 6 in Column 9) discloses further dihydronaphthalene derivatives where the 5 or 8 position (depending on the system of numbering) of the dihydronaphthalene nucleus is substituted with an alicyclic, aryl or heteroaryl group. The compounds of this reference have retinoid-like or retinoid antagonist-like biological activity.
The present invention relates to compounds of Formula 1, Formula 2 or Formula 3
where X is O, S, or (CR1R1), where n is 0, 1 or 2;
Y is a bivalent radical having Formula 4 or Formula 5 where O is an integer from 1 to 4
xe2x80x83or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatoms selected from N, S and O, said aryl or heteroaryl groups being unsubstituted, or substituted with 1 to 3 C1-6alkyl or with 1 to 3 C1-6fluoroalkyl groups;
X1 is O, S or NH;
R1 is independently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;
R2 is independently H, lower alkyl of 1 to 6 carbons, OR1, 1-adamantyl, or lower fluoroalkyl of 1 to 6 carbons, or the two R2 groups jointly represent an oxo (xe2x95x90O) group;
R3 is hydrogen, lower alkyl of 1 to 6 carbons, OR1, fluoro substituted lower alkyl of 1 to 6 carbons or halogen, NO2, NH2, NHCO(C1-C6)alkyl, or NHCO(C1-C6)alkenyl;
A is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, xe2x80x94CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CH(OR13O), xe2x80x94COR7, CR7(OR12)2, CR7(OR13O), or Si(C1-6alkyl)3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R14 is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl-C1-C10alkyl, naphthyl-C1-C10alkyl, C1-C10-alkenylphenyl having 1 to 3 double bonds, C1-C10-alkynylphenyl having 1 to 3 triple bonds, phenyl-C1-C10alkenyl having 1 to 3 double bonds, phenyl-C1-C10alkynyl having 1 to 3 triple bonds, hydroxy alkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acyl group is represented by COR8, or R14 is a 5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, said heteroatoms being selected from a group consisting of O, S, and N, said heteroaryl group being unsubstituted or substituted with a C1 to C10alkyl group, with a C1 to C10fluoroalkyl group, or with halogen, and the dashed line in Formula 4 represents a bond or absence of a bond.
In a second aspect, this invention relates to the use of the compounds of Formula 1, Formula 2, and Formula 3 for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. The compounds are also useful for the prevention and treatment of metabolic diseases such as type II diabetes and diabetes mellitus and for prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. In addition, the present compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other comeopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for the compounds of the present invention include the prevention and treatment of conditions and diseases associated with Human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil(copyright), diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
Alternatively, those compounds of the invention which act as antagonists or inverse agonists of one or more retinoid receptor subtypes are useful to prevent certain undesired side effects of retinoids which are administered for the treatment or prevention of certain diseases or conditions. For this purpose the retinoid antagonist and/or inverse agonist compounds of the invention may be coadministered with retinoids. The retinoid antagonist and inverse agonist compounds of the present invention are also useful in the treatment of acute or chronic toxicity resulting from overdose or poisoning by retinoid drugs or Vitamin A.
This invention also relates to a pharmaceutical formulation comprising a compound of Formulas 1, 2 or 3 in admixture with a pharmaceutically acceptable excipient, said formulation being adapted for administration to a mammal, including a human being, to treat or alleviate the conditions which were described above as treatable by retinoids, to be co-administered with retinoids to eliminate or reduce side effects of retinoids, or to treat retinoid or Vitamin A overdose or poisoning.